New Ways of Managing Prostate Cancer

Jahangeer M.MalikConsultant Clinical Oncology

7th November 2013

BASICS

PROSTATE

DOSE

TUMOUR CONTROL

TOXICITIES

Radiotherapy Chemotherapy

RADIOTHERAPY

A)Radical RadiotherapyProstate external beam radiotherapy (EBRT)LDR seed brachytherapyHDR brachytherapy boostB)Palliative prostate radiotherapyStrontium-89Radium-223

Risk profilesPROGNOSTIC CATEGORIES

PROGNOSTIC FEATURES

5 YEAR PSA RELAPSE FREE SURVIVAL

GOOD PROGNOSIS T1-2a AND PSA ≤10 ANDGLEASON SCORE ≤6

85%

INTERMEDIATE PROGNOSIS

ONE OF THE PROGNOSTIC INDICATORS RAISED

65%

POOR PROGNOSIS TWO OF THE PROGNOSTIC INDICATORS RAISED

35%

PROSTATE EXTERNAL BEAM RADIOTHERAPY

RADICAL PROSTAE RADIOTHERAPY

EBRTAdvantages• Suitable for most pts

• Including locally advanced disease T3 and nodal disease

• Don’t need GA

• Acute and late bowel and bladder toxicities

Disadvantages• Prolonged course of Rx 37#

over 7.5 weeks or 19# over 4 weeks

• Doesn’t help obstructive symptoms (may need TURP first)

• PSA follow up

Conformal radiotherapy plan

Sacrum

Rectum

Collimator leaves positioned to shape of target inserted into beam

Open (conventional)rectangular field

Pubis

Target (prostate + margin)

CRT vs IMRT

Beam profile #1

Beam profile #2 Beam

profile #3

Dose intensity

PTV

RO

PTV

RO

3-field RT 3-field IMRT

Prescribed dose (typical distribution)

With IMRT, dose distribution can be shaped to the target to spare organs at risk

Intensity-modulated radiotherapy

RO: risk organPTV: planning target volume

IMRT/hypofractionation

• CHHIP study• 57Gy/19f vs 60Gy/20f vs 74Gy/37f• Conformal IMRT• Toxicity reported at median follow up for

50.5m• Await for bPFS and OS outcome

David Dearnaley et al Lancet Oncol 2012; 13: 43–54

CHHiP ……Acute Toxicity

RTOG 18W

74Gy(N=129)

57Gy(N=129)

60Gy(N=132)

GI≥2 3 (2.3%) 1 (0.8%) 3 (2.3%)

GU≥2 9(7%) 9 (7%) 10 (7.6%)

David Dearnaley et al Lancet Oncol 2012; 13: 43–54

CHHiP ……Late ToxicityBowel Bladder

RTOG 2Y 74Gy(N=138)

57Gy(N=143)

60Gy(N=137)

UK STANDARD

GI≥2 6 (4.3%) 2 (1.4%) 5 (3.6%) 20%

GU≥2 3(2.2%) 0(0%) 3 (2.2%) 8%

RT01 study (64Gy/32f vs 74Gy/37f) RTOG≥2 GU=8% and GI=20% at 2y

Progress at ECC

• Currently treating 80% patients/week with VMAT-IMRT.

• Plan to treat all with IMRT in 6months time.• Plan to treat prostate and pelvis with IMRT for

high risk patients in next 2 years time.

LDR SEED BRACHYTHERAPY

RADICAL PROSTATE RADIOTHERAPY

Brachytherapy the ultimate dose escalated IMRT

Permanent LDR Iodine 125 seeds

Temporary Iridium 192 HDR implant

D-LDR brachytherapy

Criteria

•T1-T2b

•Vol<70cc

•No TURP

•Flow >10ml/sec,RV<150ml

•GS6+PSA≤20 or Gs7+PSA≤15 or GS9-10 and PSA≤10

Advantages of Intraoperative

D90 = dose to 90% of the prostate

Correlates with PSA RFS

Day case single visit

Can adjust plan on the day and calculate dose

D100 = 145Gy- 100% 3mm

D150 = 217Gy- 60-70% PTV

D60 = 100Gy = 2cc rectum

Safely boost biopsy +ve sites

Helps avoid excess dose to critical areas

ADVANTAGES• Very high radiation dose 145Gy to

prostate• <1% risk of incontinence• 70% potency rates

DISADVANTAGES/Side effects

• Main side effect - urethritis up to 9-12 months

• Proctitis 5% & Stricture 5-10%

• PSA falls slowly & can bounce causing anxiety for patients

Long term outcome data

Blasko 347 pts 15 yr PFS 86%

Potters 1449 pts 12 yr PFS 89%

Stock & Stone

1561 pts 10 yr PFS 96%

Leeds 1141pts 10 yr PFS 95%

Progress at ECC

Treated 500 patients over last 7 years

Catheterization rate<5%

LR outcome=95% PSA control rate,

IR=85% and HR(GS8/PSA>20)=75%

(CHRISTIE DATA)

Final decision All Patients Localised

Radical Radiotherapy 55 46

AM/AS/WW 54 54

Brachytherapy 32 32

Prostatectomy 52 52

Palliative Radiotherapy NR NR

Hormone therapy 54 11

Other 1 1

Total 248 196

Patients Diagnosed in 2011 who had an oncology consultation and treatment chosen

All Patients Localised

Radical Radiotherapy 97 30

AM/AS/WW 40 38

Brachytherapy 31 28

Prostatectomy 28 25

Palliative Radiotherapy 21 0

Hormone therapy 10 1

Other 7 1

Total 234 123

2012

HDR BRACHYTHERAPY BOOST

RADICAL PROSTAE RADIOTHERAPY

Started late 1990’s

High dose rate HDR Brachytherapy

Usual indication for HDR is a boost

• Where there is a significant predictive risk of extra capsular or seminal vesicle involvement:

External beam

Brachytherapy

•Very high dose per fraction

•Single 15Gy

•Reduced irradiated volume

•Shortened number of XRT visits (15fractions rather 37)

DisadvantagesInpatient treatment

Catheter discomfort

Relatively medically labour intensive

Advantages of HDR

UK Standard

ChristieMartinez

EBRT

Dose (Gy) 74 37.5 46

Number of Fractions 37 15 23

HDR

Dose (Gy) 15 23

Number of Fractions 1 2

2 Gy Equivalence 74 113.6 131.4

HDR----Best Dose-escalation

HDR is the future?

•Combine with functional imaging to boost, alter RT

•ECC will start HDR prostate from next year

STRONTIUM-89RADIUM-223

PALLIATIVE PROSTATE RADIOTHERAPY

4)Strontium-89

• Bone seeking beta rays emitter(electron)• Single IV for bone pains• Maximum range in tissues=8mm• RR=80%• Time to response=7-20days• Duration of response=2months• Toxicity=pain flare, bone marrow suppression

EurJ Cancer, Vol. 27, No. 8, pp. 954-958, 1991

4)AlphaRadin (Radium 223)

• Bone seeking α emitter• IV• T1/2 11.4 days• <100µm range

Phase 3 trial closed early due to significant survival benefit in favour of Ra 223 reported at ECCO Stockholm sep 2011

46 vs 65w

P=0.017

ECCO 2011 P3 Interim analysis(ALSYMPCA)

• 922 cases with CRPC and bone mets• 2:1 randomisation with placebo.• 4weekly×6• OS 14 m vs 11.2m (P=0.022, HR 0.69)• Well tolerated ( G3-4 neutropenia 1.8% vs

0.8%)

Future..

you can see!

IMRT/VMATHDR prostate boostRadium -223 radio-isotope treatment

CHEMOTHERAPY

PROSTATE CANCER TRIALS FOR MORE ADVANCED DISEASE

CRPC

3rd Line estrogense.g.

Diethylstiboestrol

2nd line AAe.g. Bicalutamide

1st line LHRHae.g. Zoladex

DOCETAXELChemotherapy

Trials

Low dose SteroidsDexamethasone Or Prednisolone

New reported trials

After Docetaxel in CRPC

DOCETAXEL

After DOCETAXEL

PROSTATE CANCER TRIALS FOR MORE ADVANCED DISEASE

CRPC

RR=85%,Median duration of response=18-24m

3rd Line estrogense.g.

Diethylstiboestrol

2nd line AAe.g. Bicalutamide

1st line LHRHae.g. Zoladex

DOCETAXELChemotherapy

Trials

Low dose SteroidsDexamethasone Or Prednisolone New reported

trialsAfter Docetaxel

in CRPC

RR=30-40%Median duration of response=3-6m

RR=30%Median duration of response=3-6m

Dex 0.5mg OD,RR 50%,MDR=7mPred 10mgOD,RR30%,MDR=2-3m

Abiraterone

Newer Drugs

2) Abiraterone (Hormone therapy)

3)Denosumab

(Bone)

Enzalutamide

(Hormone therapy)

5) Sipuleucel-T

(Vaccine)

1) Cabazitaxel

(ChemoTherapy)

1)Cabazitaxel

• Tried in patients after Docetaxel.• Diarrhoea, Neutropenia and sepsis.• Survival benefit=2.4m• Available in England• Rejected by SMC

2)Abiraterone

AA 797 736 657 520 282 68 2 0Placebo 398 355 306 210 105 30 3 0

21

HR = 0.646 (0.54-0.77) p < 0.0001

Placebo 10.9 months (95% CI: 10.2-12.0)

AA 14.8 months (95% CI: 14.1-15.4)

100

80

60

40

20

Sur

viva

l (%

)

00 3 6 9 12 15 18

Time to Death (Months)

de Bono et al. Ann Oncol 2010; 21 (10 suppl 8): Abstract LBA5 (oral presentation)Scher et al. J Clin Oncol 2011; 25 (suppl 7): Abstract 4 (oral presentation)

3)Denosumab

Adapted from Roodman D. N Engl J Med. 2004;350:1655.

PTHrP, BMP,TGF-β, IGF, FGF,VEGF, ET1, WNT

Osteoblasts

Inactivate Osteoclast

PDGF, BMPsTGF-β, IGFs

FGFs

Tumor Cell

CA+2

RANKL

RANK

Denosumab

Bone Resorption Inhibited

RANK ligand (RANKL) key mediator for osteoclast formation, function, survival

Potential target for treating bone metastasis

4)Sipuleucel-T (Vaccine)

Immature monocytes thought to mature to fully competent antigen presenting cells (APC), presenting PAP peptides in the patient activates CD4+ and CD8+ T cells

Drake et al. Nature Immunol Rev 2010; 10(8): 580-593

5)Enzalutamide

• Oral hormone tablet• Trial in post-docetaxel chemo patients• 4.8m survival benefit• Awaiting SMC approval, likely to be approved.

After DOCETAXEL

PROSTATE CANCER TRIALS FOR MORE ADVANCED DISEASE

CRPC

RR=85%,Median duration of response=18-24m

3rd Line estrogense.g.

Diethylstiboestrol

2nd line AAe.g. Bicalutamide

1st line LHRHae.g. Zoladex

DOCETAXELChemotherapy

Trials

Low dose SteroidsDexamethasone Or Prednisolone New reported

trialsAfter Docetaxel

in CRPC

RR=30-40%Median duration of response=3-6m

RR=30%Median duration of response=3-6m

Dex 0.5mg OD,RR 50%,MDR=7mPred 10mgOD,RR30%,MDR=2-3m

Abiraterone

12m+

Thank you all